Non-ocular circadian clock resetting in humans

ABSTRACT

A method for resetting the phase of the human circadian clock and for enhancing alertness and performance in humans is disclosed. The method involves the application of non-solar photic stimulation, in the range of 15 to 150,000 lux, to any non-ocular region of the human body during wakefulness or during sleep. Preferably, the photic stimulation has a wavelength within the visible spectrum (˜400-750 nm). The method can be used to both delay and advance the circadian clock according to a phase response curve (PRC). The method may also be used for acute/immediate enhancement of alertness and performance. The method is applicable to alleviation of problems associated with “jet-lag”, shift work sleep disturbance, and other sleep disturbances involving misalignment of circadian rhythms. The method provides a novel technique for shifting the phase of the circadian clock, and enhancing alertness and performance, using existing, or newly-developed devices.

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/656,409 filed Sep. 6, 2000, which is a divisional of U.S.patent application Ser. No. 09/074,455, filed May 7, 1998, now U.S. Pat.No. 6,135,117, which claims the benefit of U.S. Provisional ApplicationNo. 60/046,188 filed May 12, 1997, and U.S. Provisional Application No.60/072,121 filed Jan. 22, 1998.

[0002] This invention was made with Government support under GrantNo(s). R01MH45067 and K02MH01099, awarded by the National Institute ofHealth. The Government has certain rights in the inventions.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] This invention relates to a method for resetting the phase of thehuman circadian clock and for enhancing alertness and performance inhumans by application of non-solar photic stimulation, in the range of15 to 150,000 lux, to any non-ocular region of the human body.

[0005] 2. Related Art

[0006] As with all vertebrates, humans exhibit temporal organization inbehavior and in numerous physiological functions. In response to thenatural alternation in light and dark, virtually all species havedeveloped endogenous rhythms with frequencies close to 24 hours. Theseinternally generated, self-sustaining rhythms are known as circadianrhythms (from the Latin circa=about, and dies=day). The pervasive natureof such rhythms suggests that circadian temporal organization is vitalto the overall well-being of the organism. Numerous systems andfunctions are mediated by the circadian system including hormonaloutput, body temperature, rest and activity, sleep and wakefulness, andmotor and cognitive performance. In all, literally hundreds of circadianrhythms in mammalian species have been identified.

[0007] Left to run at its inherent frequency, the human biological clockthat is responsible for the generation of circadian rhythms exhibits adaily periodicity of slightly longer than 24 hours. Thus, a dailycorrection to the clock must be made for our internal rhythms to remainsynchronized or ‘entrained’ to the natural 24 hour day. It is widelyaccepted that exposure to the natural light/dark cycle provides thestrongest signal to entrain the human circadian system to thegeophysical day. Inadequate exposure to light of sufficient intensity isa contributing factor in disorders associated with biological rhythmdisturbance, such as seasonal affective disorder (SAD), jet lag fromtransmeridian travel, shift work and some types of insomnia (advancedand delayed sleep phase syndromes). Timed exposure to artificial brightlight to the eyes has been used successfully to treat such disorders.Some examples of studies relating to the effects of timed ocularexposure to artificial bright light are discussed in U.S. Pat. Nos.5,167,228 and 5,176,133 to Czeisler, which are herein incorporated byreference.

[0008] There is compelling evidence that bright ambient illumination onthe eyes can have an immediate, acute enhancing effect on alertness andperformance. By way of example, the article entitled, “Enhancement ofNighttime Alertness and Performance with Bright Ambient Light” by ScottS. Campbell and Drew Dawson in Physiology & Behavior Vol. 48, pp.317-320, 1990, demonstrates that ocular exposure to illumination ofabout 1,000 lux enhances a human's alertness and performance. Thisnon-circadian property of light exposure is of particular relevance topeople who must work night or rotating shift work schedules, sincedeclines in alertness and performance may result in increased accidentrates, reduced productivity and increased health care costs.

[0009] It is widely accepted that the mammalian circadian clock which islocated in the brain, within the suprachiasmatic nuclei (SCN) of thehypothalamus, receives photic information via the eyes, by visual and/ornon-visual ocular pathways originating in the retina. It is also widelyacknowledged that light acts to enhance alertness and performance via anocular route(s). Yet, it has been recognized for decades that manyspecies of birds and reptiles possess extra-ocular photoreceptors, andit has been demonstrated that circadian and photoperiodic response tolight can be mediated entirely by such photoreceptors. In contrast, itis generally assumed that such nonvisual circadian photoreceptors inmammals reside within the retina, and that mammals do not possess thecapacity for extraocular circadian photoreception. This conclusion isbased on studies showing a failure of several rodent species to entrainto a light/dark cycle, or to respond to pulses of light with shifts incircadian phase, following complete optic enucleation.

[0010] Perhaps because of the widespread acceptance of the notion thatmammals have no capacity for extraocular circadian photoreception, onlytwo studies have examined whether extraocular light exposure can impactbrain functioning in humans. In a study of blind subjects, Czeisler andcoworkers found an absence of light-induced melatonin suppression duringocular shielding in two individuals who did show melatonin suppressionwhen light fell on their eyes. A decade earlier, Wehr and coworkersreported a lack of clinical response in seasonal affective disorder whenpatients' skin (face, neck, arms and legs) was exposed to a bright lightstimulus (2500 lux) while their eyes were shielded. No study hasexamined specifically whether circadian phase resetting can be achievedin humans via extraocular pathways.

[0011] As noted above, ocular exposure to timed bright light has beenshown to be an effective remedy for circadian rhythm disorders.Unfortunately, treatment regimens involving ocular exposure to brightlight are tedious and time-consuming. Many patients are simply unwillingor unable to remain relatively stationary for extended periods gazing ata bright light stimulus.

[0012] Additionally, the nature of the phase response curve to lightdictates that the largest shifts, both advances and delays, are achievedat times during which people are typically asleep. Thus, all but themost committed users of bright light treatments fail to benefit from themost efficient temporal application of the intervention. Attempts havebeen made to remedy these problems by the development of ‘light visors’,which are devices worn like a cap that are intended to permit the usermore freedom of movement while receiving light exposure. In practice,such devices are likely to be poorly received since they also directlight toward the eyes, and therefore, limit the visual field.

[0013] Also, as noted above, ocular light exposure has been demonstratedto improve alertness and performance. Unfortunately, as with circadianclock resetting, the use of ocular light in this capacity hasconsiderable drawbacks. By way of example, the implementation of brightambient light is likely to be impractical for use in typical industrialcontrol room settings. Rapidly increasing utilization of computertechnology for monitoring and controlling plant operations calls forambient lighting conditions that take into consideration the effects ofglare and contrast on computer displays.

[0014] In summary, because light must still enter through the eyes,unrestricted vision cannot be achieved, and mobility is limited. Simply,any device that successfully gets light to the eyes, is likely tointerfere with normal activities. The result is reduced compliance andlimited effectiveness of light treatment interventions as currentlyapplied.

SUMMARY OF THE INVENTION

[0015] The present invention is a method for resetting the phase of thehuman circadian clock, or enhancing alertness and performance in humans,by application of non-solar photic stimulation, in the range of 15 to150,000 lux, to any non-ocular region of the human body. Preferably, thenon-solar photic stimulation is substantially, if not solely, applied toa non-ocular region or regions. While there is substantial evidence thatthe human circadian clock can be reset with light exposure to the eyes,this is the first demonstration that circadian clock resetting can beachieved via non-ocular phototransduction.

[0016] The present invention is premised on the unexpected result thatsubstantially non-ocular presentation of appropriately timed light inhumans can induce circadian clock resetting. Specifically, bright lighttransmitted through the skin, in a manner that rules out the possibilityof ocular photoreception, results in significant clock resetting. Asystematic relationship exists between the timing of the non-ocularlight stimulus and the magnitude and direction of phase shifts,resulting in a phase response curve. This unexpected result alsounderlies another component of the present invention—that non-ocularlight exposure enhances alertness and performance. That is, it isreasonable to conclude that non-ocular light exposure has the samephysiological consequences as ocular exposure whether impacting on thebiological clock, or on other brain areas involved in maintenance ofoptimal alertness and performance.

[0017] These methods provide a number of advantages over the way inwhich ocular light exposure is applied for the purposes of resetting thecircadian clock and enhancing alertness and performance. For example,non-ocular light can be administered in much less obtrusive ways by notrestricting vision and mobility; patients are not required to remainstationary and to stare at lights for extended periods. Likewisenon-ocular light removes the inconvenience and potential hazardsassociated with glare and eye fatigue. Another advantage of theinvention is that non-ocular light exposure can be used by individualsfor whom ocular light exposure is contraindicated. This group includes,but is not restricted to, individuals with glaucoma, corneal pathology,progressive retinal disease and cataracts. In addition, it is clear thatblind individuals, with no ocular light perception, could benefitconsiderably from non-ocular light treatments, since many of theseindividuals are unable to remain synchronized to the environmentallight/dark cycle.

[0018] Perhaps the most important advantage of this invention is that itenables light treatments to be administered during sleep. The nature ofthe phase response curve to light in humans dictates that the largestshifts, both advances and delays, are achieved at times during whichpeople are typically asleep. That is, phase delays occur when light isadministered during the late subjective night (within a several-hourwindow prior to the daily minimum in body temperature), whereas phaseadvances are achieved when light exposure occurs during the earlysubjective morning (within a several-hour window following the dailyminimum in body temperature). One advantage of the invention is that itpermits delivery of non-ocular light near the temperature minimumwithout requiring wakefulness, thus insuring maximum phase shifting.

[0019] One embodiment of the invention is a method for resetting thehuman circadian clock, comprising the steps of exposing the poplitealregion of an awake human subject to light at preselected times based onthe human phase response curve to non-ocular light. The result is arapid phase delay or advance with the intention of resetting thecircadian clock to the desired new phase.

[0020] Another embodiment of the invention is a method for resetting thehuman circadian clock, comprising the steps of exposing any non-ocularregion of an awake human subject to light at preselected times based onthe human phase response curve to non-ocular light. The result is arapid phase delay or advance with the intention of resetting thecircadian clock to the desired new phase.

[0021] Another embodiment of the invention is a method for resetting thehuman circadian clock, comprising the steps of exposing the poplitealregion of a sleeping human subject to light at preselected times basedon the human phase response curve to non-ocular light presented duringsleep. The result is a rapid phase delay or advance with the intentionof resetting the circadian clock to the desired new phase.

[0022] Another embodiment of the invention is a method for resetting thehuman circadian clock, comprising the steps of exposing any non-ocularregion of a sleeping human subject to light at preselected times basedon the human phase response curve to non-ocular light presented duringsleep. The result is a rapid phase delay or advance with the intentionof resetting the circadian clock to the desired new phase.

[0023] Another embodiment of the invention is a method for enhancingalertness and/or performance, comprising the steps of exposing thepopliteal region of an awake human subject to light at times whenenhanced alertness and/or performance is desired. The result is animmediate and acute increase in subjective and physiological levels ofalertness and performance.

[0024] Another embodiment of the invention is a method for enhancingalertness and/or performance, comprising the steps of exposing anynon-ocular region of an awake human subject to light at times whenenhanced alertness and/or performance is desired. The result is animmediate and acute increase in subjective and physiological levels ofalertness and performance.

[0025] Another embodiment of the invention is an apparatus that canadvantageously administer light to a non-ocular region of a human. Theapparatus may be a stationary device such as a fiber optic phototherapysystem, or it may be a portable device, such as a battery-powered lightemitting diode (LED) array.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026]FIG. 1 is a perspective view of a device used to expose anon-ocular region of a human subject to light in order to reset thecircadian clock or enhance alertness and/or performance, using themethod in accordance with the present invention;

[0027]FIGS. 2A and 2B are graphs illustrating a delay in the circadianphase marker of minimum body temperature in one human subject inducedusing the method in accordance with the present invention;

[0028]FIGS. 3A and 3B are graphs illustrating an advance in thecircadian phase marker of minimum body temperature in one human subjectinduced using the method in accordance with the present invention;

[0029]FIG. 4A is a graph illustrating the response of the endogenouscircadian clock as measured by body temperature in a group of humansubjects, induced by a single three-hour presentation of bright light tothe popliteal region of subjects using the method in accordance with thepresent invention;

[0030]FIG. 4B is a graph illustrating the response of the endogenouscircadian clock as measured by dim-light melatonin onset in a group ofhuman subjects induced by a single three-hour presentation of brightlight to the popliteal region of subjects using the method in accordancewith the present invention;

[0031]FIG. 4C is a graph illustrating the response of the endogenouscircadian clock as measured by body temperature, in a group of humansubjects, to a sham experimental condition (no light presented);

[0032]FIG. 5A is a graph illustrating nighttime temperature profiles ofone human subject before (dotted line) and after (solid line) threehours of exposure to a 10,000 lux, broad-band white light stimuluspresented to the popliteal region between 2400 h and 0300 h on oneoccasion;

[0033]FIG. 5B is a graph illustrating nighttime melatonin onsets of onehuman subject before (dotted line) and after (solid line) three hours ofexposure to a 10,000 lux, broad-band white light stimulus presented tothe popliteal region between 2400 h and 0300 h on one occasion;

[0034]FIGS. 6A and 6B are graphs illustrating a delay in the circadianphase marker of minimum body temperature in one sleeping human subjectinduced using the method in accordance with the present invention; and

[0035]FIGS. 7A and 7B are graphs illustrating an advance in thecircadian phase marker of minimum body temperature in one sleeping humansubject induced using the method in accordance with the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0036] A method for resetting the phase of the human circadian clock andfor enhancing alertness and performance in humans is disclosed. Themethod involves the application of non-solar photic stimulation to anynon-ocular region of the human body. The preferred embodiment of theinvention involves non-ocular exposure to light in a range from about 15minutes to about 12 hours, and most preferably for a duration of 3hours. Preferably the photic stimulation has an intensity in the rangeof 15 to 150,000 lux, and most preferably in a range from 10,000 to13,000 lux. Preferably, the photic stimulation has a wavelength withinthe visible spectrum (˜400-750 nm), and most preferably within theblue-green bandwidth (˜455-540 nm). Preferably, the non-solar photicstimulation is substantially, if not solely, applied to a non-ocularregion or regions. The method can be used on a sleeping human subject.The method can be used to both delay and advance the circadian clockaccording to a phase response curve (PRC). The method may also be usedfor acute/immediate enhancement of alertness and performance. The methodis applicable to alleviation of problems associated with circadianrhythm sleep disorders, such as with “jet-lag” from transmeridiantravel, shift work sleep disorder, advanced sleep phase syndrome,delayed sleep phase syndrome, non-24 hour sleep-wake disorder, irregularsleep-wake pattern, circadian rhythm disorders associated withblindness, circadian rhythm disorders in individuals for whom ocularlight exposure is contraindicated, and other sleep disturbancesinvolving misalignment of circadian rhythms. The method provides a noveltechnique for shifting the phase of the circadian clock, and enhancingalertness and performance, using existing, or newly-developed devices.

[0037] Empirical Basis for Clock Resetting with Non-Ocular LightExposure

[0038] Circadian rhythms are endogenously generated oscillations ofabout twenty-four hours that provide temporal structure to a wide rangeof behavioral and physiological functions. Because the endogenous clocktends to run at a period close to, but not exactly 24 hours, a dailyadjustment is required to synchronize, or entrain circadian rhythms tothe external environment. The natural light/dark cycle is the mostimportant signal for ensuring such entrainment, and many vertebrate andnon-vertebrate species possess multiple photoreceptor systems throughwhich circadian entrainment may be achieved. In the house sparrow, forexample, three discrete input pathways for light to act on the circadiansystem have been identified. Similarly, a number of fish, amphibian andreptile species have extraocular and extrapineal pathways for circadianlight transduction. Indeed, a host of species possess functionalextraocular pathways for circadian entrainment by light, even in thepresence of ocular photoreceptors that are capable of mediating theentraining influence of light.

[0039] In recent years, it has been suggested that the photoreceptorsresponsible for entraining the mammalian biological clock may not be thesame cells that mediate vision. It has been shown, for example, thatmice homozygous for the autosomal recessive allele rd (“retinallydegenerate”), with no electrophysiological or behavioral visualresponses to bright light, can be entrained to a light/dark cycle.Likewise, bright light exposure suppresses melatonin output in sometotally blind human subjects, despite the fact that they have noconscious light perception and no pupillary light reflex. Such findingssupport the hypothesis that all vertebrates, including mammals, havespecialized nonvisual photoreceptors that mediate circadian responses tothe light-dark cycle. It is generally assumed, however, that suchnonvisual circadian photoreceptors in mammals reside within the retina,and that mammals do not possess the capacity for extraocular circadianphotoreception. This conclusion is based on studies showing a failure ofseveral rodent species to entrain to a light/dark cycle, or to respondto pulses of light with shifts in circadian phase, following completeoptic enucleation.

[0040] Perhaps because of the widespread acceptance of the notion thatmammals have no capacity for extraocular circadian photoreception, onlytwo studies have examined whether extraocular light exposure can impactbrain functioning in humans. In their study of blind subjects, Czeislerand coworkers found an absence of light-induced melatonin suppressionduring ocular shielding in two of their subjects who did show melatoninsuppression when light fell on their eyes. A decade earlier, Wehr andcoworkers reported a lack of clinical response in seasonal affectivedisorder when patients' skin (face, neck, arms and legs) was exposed toa bright light stimulus (2500 lux) while their eyes were shielded.Detailed examination of the methods used in these studies makes it clearthat they did not adequately test the ability of the human circadiantiming system to respond to non-ocular light; in neither study was theoutput of the circadian clock actually measured. Likewise, there areproblems of interpretation in most studies using non-human mammals.Furthermore, the comparative literature on circadian rhythms indicatesthat in a vast majority of instances, there is no fundamental differencein the manner in which mammalian and non-mammalian species respond tomanipulations of the circadian clock. For these reasons, we decided tore-examine the issue of extraocular photoreception in humans.

[0041] Method for Non-Ocular Circadian Clock Resetting in Humans

[0042] Set forth below are some examples of using the method to resetthe circadian clock in human subjects via a non-ocular pathway. Thefirst two examples involve subjects who were awake during the non-ocularlight exposure interval; the third example describes effects ofnon-ocular light exposure in sleeping subjects.

EXAMPLE 1

[0043] A total of 33 phase-shifting trials was carried out in 15 healthysubjects (mean age: 35.7 years; range: 22-67; 13 males, 2 females). Eachlaboratory session lasted for four consecutive days and nights, duringwhich subjects were assigned randomly to either a control or an activecondition. Successive laboratory visits were separated by at least 10days. During the active sessions (phase delay, n=13; phase advance,n=11), light was presented at varying times relative to baselinecircadian phase, in order to examine the response of the circadian clockthroughout the 24-hour circadian cycle. A circadian cycle is onecomplete cycle of a circadian variable, such as body temperature. Undernormal conditions a circadian cycle is about twenty-four hours. Lightcan be applied during one or more circadian cycles. The extraocularlight stimulus in this example comprised a 3-hour pulse of lightpresented to the popliteal region, the area directly behind the kneejoint.

[0044] In this particular example, the light source 10 was a BiliBlanketPlus (Ohmeda, Inc.), a fiber optic phototherapy device commonly used forhome treatment of hyperbilirubinemia, as shown in FIG. 1. The lightsource 10 includes a halogen lamp (not shown) in a vented metal housing12, which also contains a small fan to disperse heat generated by thelamp. Illumination from the halogen bulb leaves the housing 12 via 2400optic fibers encased in a flexible plastic tube 14 about one meter (m)in length. The optic fibers terminate in a 4″×6″ woven pad 16approximately 0.25″ thick. Because the light source 10 is remote, thefiber optic pad 16 generates no heat. The pad 16 was placed over thepopliteal area of each leg which has ample surface vasculature andsecured in place with a polyester athletic knee brace. During the 3-hourlight exposure interval, subjects remained seated in a reclining chair,with a table positioned over their laps.

[0045] To ensure that the light stimulus did not reach the retina, a10′×10′ black, opaque, double thickness polyester “skirt” was drapedover the table, reaching the floor on all sides, and was secured withVelcro around the subject's waist. An exhaust fan (in addition to thosein each BiliBlanket housing) was placed beneath the skirt to evacuateany heat produced by the halogen light source. The lamp housing 12 wasplaced beneath the table and under the skirt, so that any light escapingthrough the housing vents was obscured from the subject's eyes.Illumination at the subject's eye level never exceeded 20 lux.Accordingly, the illumination from light source 10 is substantiallyapplied to a non-ocular region. Throughout their stay in the laboratory,when not sleeping and not involved in the experimental lightmanipulation, subjects were maintained in constant illumination of lessthan 50 lux.

[0046] Each light source 10 provided approximately 13,000 lux to thepopliteal region in a bandwidth between approximately 455 and 540 nm.Although in this example one type of light source 10 operating within aparticular bandwidth and at a particular intensity is disclosed, othertypes of light systems with other bandwidths and other intensities, suchas broad-band white light provided by commercial fluorescent lightboxes, may be used as needed or desired (see Example 2, below).

[0047] On the night prior to (night 1 in the lab) and the nightsfollowing the light stimulus (nights 3 and 4) subjects were required toremain in bed (and were allowed to sleep) from 2400 h until noon thefollowing day. On the light exposure night (night 2 in the lab) sleepwas necessarily displaced to accommodate presentation of the 3-hourlight pulse. With the exception of this interval, subjects were in bedfrom 2400 h until noon on night 2, as well. Sleep was not permittedduring the light exposure interval and continuous EEG and videomonitoring of subjects throughout the exposure interval ensuredcompliance.

[0048] Body core temperature was recorded continuously. In a subset ofsessions (n=18), hourly saliva samples were also collected for melatoninassay. Body core temperature was recorded in 2-minute epochs, usingdisposable rectal thermistors (Yellow Springs, Inc.) attached toMiniLogger ambulatory recording devices (Mini-Mitter, Inc., Sun River,Oreg.). Saliva samples were collected under dim light from 1800 h until2400 h on night 2 (prior to light exposure) and on night 4.

[0049] Melatonin levels were measured by radioimmunoassay (ALPCO, Inc.,Windham, N.H.) using the Kennaway G280 antibody. All samples from agiven subject during a given laboratory session were analyzed in thesame assay. We have calculated an intraassay coefficient of variation of2.1%; the inter-assay precision has been reported as 10.4%.

[0050] The nadir of the temperature rhythm and the dim light melatoninonset (DLMO) were used to evaluate circadian phase prior to andfollowing presentation of the light pulse. The magnitude of phase shiftachieved in each trial was determined by comparing subjects' baselinecircadian phase (during the first 24 hours in the lab), with phasedetermined during the final 24 hours in the lab.

[0051] Referring to FIGS. 2A and 2B, an example of a delay in circadianphase in one subject in response to a 3-hour bright light presentationto the popliteal region is illustrated. Light was presented on oneoccasion between 0100 h and 0400 h on night 2 in the laboratory (blackbar) while the subject (a 29 year-old male) remained awake and seated ina dimly lit room (ambient illumination<20 lux). Circadian phase wasdetermined by fitting a complex cosine curve (dotted line) to the rawbody core temperature data (solid line). Resulting phase estimates areindicated by vertical dotted lines. Baseline (night 1) circadian phaseoccurred at 0404 h as shown in FIG. 2A; circadian phase following lightpresentation (last 24 hours in the lab) occurred at 0708 h as shown inFIG. 2B. The phase angle between the mid-point of the light stimulus andthe fitted body temperature minimum at baseline was 1.57 hours. Theresulting phase delay was 3.06 hours.

[0052] Referring to FIGS. 3A and 3B, an example of an advance incircadian phase in one subject in response to a 3-hour bright lightpresentation to the popliteal region is illustrated. Light was presentedon one occasion between 0600 h and 0900 h, following night 2 in thelaboratory (black bar) while the subject (a 44 year-old male) remainedawake and seated in a dimly lit room (ambient illumination<20 lux).Circadian phase was determined by fitting a complex cosine curve (dottedline) to the raw body core temperature data (solid line). Resultingphase estimates are indicated by vertical dotted lines. Baseline(night 1) circadian phase occurred at 0713 h as shown in FIG. 3A;circadian phase following light presentation (last 24 hours in the lab)occurred at 0453 h as shown in FIG. 3B. The phase angle between themid-point of the light stimulus and the fitted body temperature minimumat baseline was 0.28 h. The resulting phase advance was 2.34 hours.

[0053] Response of the endogenous circadian pacemaker, as measured bybody core temperature to a single 3-hour presentation of bright light tothe popliteal region is illustrated in FIG. 4A. Each point representsthe phase shift observed (advances are designated by positive numbers,delays by negative numbers on the y-axis) in response to bright lightpresented at a given time relative to the phase of body core temperatureat baseline. “Timing of light relative to Tmin” (x-axis) refers to theinterval between the mid-point of light presentation and the fittedtemperature minimum. Magnitude of the observed phase shifts variedsystematically as a function of this relationship, resulting in thegeneration of a classic phase response curve.

[0054] In 18 of trials, the phase response of a second circadian marker,the onset of the endogenous melatonin rhythm under dim light conditions(DLMO) was assessed. The results of these assessments are shown in FIG.4B. Each point represents the phase shift observed (advances aredesignated by positive numbers, delays by negative numbers on they-axis) in response to bright light presented at a given time relativeto the phase of body core temperature at baseline.

[0055] “Timing of light relative to Tmin” (x-axis) refers to theinterval between the mid-point of light presentation and the fittedtemperature minimum. As with body temperature, the timing of humansubjects' nightly melatonin onset was shifted by the non-ocular lightstimulus according to a phase response curve. The direction andmagnitude of the shifts in DLMO were equivalent to those fortemperature. Indeed, there was a significant correlation between theshift in body core temperature and the shift in melatonin onset(Spearman rank-order correlation: rho=0.704; P=0.009). The strongcorrelation between the two phase markers employed strongly suggeststhat the non-ocular light stimulus directly influenced the endogenouscircadian clock and not simply the output variables.

[0056] The phase shifts in the active sessions were the consequence ofthe light administration, and not systematically influenced by theexperimental procedure itself. In the control condition, subjectsunderwent the identical protocol as in the delay condition, includingapplication of the fiber optic pad and activation of the exhaust fans.However, in the control condition, the halogen bulb providingillumination to the optic pad was disconnected. Because in allconditions the light source was not turned on until they were seated andan opaque “skirt” was in place, subjects were unaware of whether lightwas actually being presented during a given session. Comparison of thephase of body temperature at baseline and following the controlmanipulation revealed no systematic phase shifts as a result of exposureto this protocol, as illustrated in FIG. 4C. Each point represents thechange in phase following the control stimulus compared to baselinetemperature phase. All no-light presentations occurred prior to baselinetemperature minimum and therefore only that portion of the x-axis isshown.

[0057] Selection of the popliteal region for the site of light exposurein this study ensured (for methodological control) that light would notreach the retina. There is every reason to believe that timed lightexposure presented to any non-ocular area of the body with adequatesurface vasculature would result in similar circadian phase resetting.

EXAMPLE 2

[0058] In another example, six subjects (mean age 45.4 yrs; range, 30-71yrs) were used to examine effects of non-ocular circadian clockresetting. As in Example 1, the popliteal region (the area directlybehind the knee joint), was the site for the non-ocular lightadministration.

[0059] Illumination was provided by a light box (Apollo, Inc., OremUtah) situated directly beneath the exposed knees (i.e. subjects woreshort pants) of a subject sitting upright in a comfortable chair. At adistance of 18 inches, the light source provided about 10,000 luxillumination. The subjects' eyes were shielded from illumination by ablackout ‘skirt’ secured around the seated subject at the level of therib cage, and extending to the floor surrounding the light. There was noother light source in the room besides the television situated 2 metersaway from the subject and providing less than 5 lux at eye level. Thebright light stimulus was presented from 2400 h to 0300 h.

[0060] For the group, the average phase delay was 2.27 hrs in responseto the non-ocular bright light stimulus. Four of the 5 subjects showed adelay, with phase-shifts ranged from 1.8 hrs to 4.7 hrs (one subjectshowed no phase-shift). FIG. 5A shows pre- and post-temperature plotsobtained from one subject. The effects of the non-ocular light stimulusare apparent. This subject showed a clear phase-delay.

[0061] In this study, we also measured salivary melatonin levelscollected each hour, beginning at 1800 h and continuing until subjects'bedtimes. Thus, on the light exposure night, samples were collected from1800 h-0300 h; on the following day they were collected from 1800 h to2400 h. Melatonin profiles from the same subject whose temperature isdepicted in FIG. 5A, are shown in FIG. 5B. As with body temperature,nighttime melatonin onset showed a substantial phase-delay when measuredon the evening following the 3-hr bright light stimulus to the poplitealregion.

EXAMPLE 3

[0062] In another example, non-ocular light was administered to 10subjects while they were asleep. As in Examples 1 and 2, the poplitealregion (the area directly behind the knee joint), was the site for thenon-ocular light administration. Each laboratory session lasted for fourconsecutive days and nights. Light was presented at varying timesrelative to baseline circadian phase, in order to examine phase responsethroughout the circadian cycle. The extraocular light stimulus consistedof a pulse of light presented to the popliteal region while subjectswere sleeping. Subjects were asleep during the non-ocular lightpresentation as verified by conventional sleep laboratory techniques(electroencephalography). The magnitude of phase shift achieved in eachtrial was determined by comparing subjects' baseline circadian phase(during the first 24 hours in the lab), with phase determined during thefinal 24 hours in the lab.

[0063] Referring to FIGS. 6A and 6B, an example of a delay in circadianphase in one subject (a 24 year-old male) in response to a 1.25-hourbright light presentation to the popliteal region during sleep isillustrated. Light was presented on two consecutive days between 0930 hand 1045 h (black bar) in a darkened room. Circadian phase wasdetermined by fitting a complex cosine curve (dotted line) to the rawbody core temperature data (solid line). Resulting phase estimates areindicated by vertical dotted lines. Baseline (night 1) circadian phaseoccurred at 0336 h as shown in FIG. 6A; circadian phase following lightpresentation (last 24 hours in the lab) occurred at 0517 h as shown inFIG. 6B. The phase angle between the mid-point of the light stimulus andthe fitted body temperature minimum at baseline was 6.52 hours (i.e.,light was presented following the temperature minimum). The resultingphase delay was 1.68 hours. There was a corresponding delay in the onsetof the melatonin rhythm (DLMO) of 1.87 hours.

[0064] Referring to FIGS. 7A and 7B, an example of an advance incircadian phase in one subject (a 54 year-old male) in response to a3-hour bright light presentation to the popliteal region during sleep isillustrated. Light was presented on two consecutive nights between 0400h and 0700 h, (black bar) in a darkened room. Circadian phase wasdetermined by fitting a complex cosine curve (dotted line) to the rawbody core temperature data (solid line). Resulting phase estimates areindicated by vertical dotted lines. Baseline (night 1) circadian phaseoccurred at 0725 h as shown in FIG. 7A; circadian phase following lightpresentation (last 24 hours in the lab) occurred at 0545 h as shown inFIG. 7B. The phase angle between the mid-point of the light stimulus andthe fitted body temperature minimum at baseline was −1.92 h (i.e., lightwas presented prior to the temperature minimum). The resulting phaseadvance was 1.67 hours.

EXAMPLE 4

[0065] Ocular exposure to light results in increased brain electricalactivity. When EEG data are collected during ocular light exposure, thensubjected to spectral analysis (Fast Fourier Transform method), powerdensity in the higher frequency ranges (beta frequency band,approximately 21-32 Hz) is enhanced relative to EEG activity during dimlight exposure. This increase in beta activity is indicative of higherlevels of alertness, and has been associated with increased levels ofpsychomotor and cognitive performance. It is reasonable to assume thatin the same manner as non-ocular exposure results in phase shiftssimilar to those achieved with ocular light pulses, non-ocular lightexposure will also affect EEG beta activity in a manner similar toocular exposure. The following example describes a pilot study that wasundertaken to determine whether non-ocular light exposure resulted inacute increases in brain electrical activity.

[0066] Multiple samples of waking EEG data from one subject werecollected during exposure of the popliteal region to a non-ocular lightsource, and during a control condition. In the control condition,electrical power was provided to the light source, but the halogen lampproviding illumination to the fiber optic cables was unplugged. Thesubject (a 25-year-old female) was seated in a dimly lit (<20 lux) room,with a double-thickness, black polyester ‘skirt’ fastened with Velcroaround her waist. Two Biliblanket phototherapy devices were attached tothe popliteal region of each leg as described earlier in Example 1. Thedevices were placed underneath the ‘skirt’ and behind the chair in whichthe subject was seated. The halogen lamp was unplugged or plugged in bythe experimenter out of view of the subject. The black skirt ensuredthat the subject was not aware of whether the light source was activatedor deactivated. The subject was instructed as follows: “Sit as still aspossible, with your feet on the floor and arms at your side. Avoid anyhead or body movements and keep your eyes closed. We will inform youwhen you may open your eyes.” Two EEG sites (C3 and 01) were referencedto linked mastoids; impedances for all were below 2 kΩ. Three minuteintervals of EEG data were collected and digitized at a rate of 256samples per second. The three minute samples were collected in thefollowing order:

[0067] A) Eyes closed, light source activated.

[0068] B) Eyes closed, light source deactivated.

[0069] C) Eyes closed, light source deactivated.

[0070] D) Eyes closed, light source activated.

[0071] The average of the data from conditions A+D (light source ‘on’)and B+C (light source ‘off’) were used to investigate the effects ofnon-ocular light on EEG activity. After removal of visually detectedeyeblink and muscle artifact, the data set from each of the conditionswere subjected to spectral analysis (FFT), yielding the average powerdensity (μV²), in 2-second epochs. Both absolute and relative powerdensity in predefined frequency bands (delta=1.54 Hz, theta=4-7 Hz,alpha=8-13 Hz, beta1=13-20 Hz, beta2=21-32 Hz) were calculated.

[0072] Total absolute power was higher when the non-ocular light sourcewas activated relative to the control condition (15.4 vs. 10.6_V² forsite C3; 11.8 vs 6.6_V² for site 01). Relative power in the alpha (16.1vs 17.2 for site C3; 23.9 vs 24.0 for site 01) and theta (15.1 vs 15.2for site C3; 11.5 vs. 10.4 for site 01) frequency bands did not differbetween lights on and lights off conditions. However, delta power wassubstantially lower (24.0 vs. 31.6, while activity in both the low andhigh beta frequency bands was higher (23.5 vs. 17.4 for B1 at site C3;23.7 vs. 19.6 for B1 at site 01; 22.7 vs. 18.0 for B2 at site C3; 27.0vs. 22.2 for B2 at site 01) when the lights were activated.

[0073] These preliminary results indicate that non-ocular lightexposure, even when the eyes are completed shielded from the lightstimulus, may result in EEG activation at frequencies associated withhigher alertness.

[0074] Devices for Facilitating the Method

[0075] The method described herein requires that a human subject beexposed to a non-ocular light source under conditions sufficient toreset the human circadian clock, or to acutely enhance alertness andperformance. The device originally used to reduce the method topractice, as described in the examples above, can be altered in a numberof ways to facilitate various applications of the method. The inventionenvisions several different means by which the light may be transmitted,including fiber optic configurations, light emitting diode (LED) arrays,bioluminescent derivations, and incandescent and fluorescent lightsources.

[0076] The invention envisions the use of these various light sourcesdesigned to facilitate light exposure to a wide range of non-ocularsites. For example, a device is envisioned by which the foot or hand iscovered (like a sock or glove), thereby exposing the entire area toillumination; another device is one by which the tympanic membrane isilluminated by LEDs incorporated in headphones or earplugs; anotherdevice is one by which the midriff is exposed to light by an illuminatedwrap; another device is envisioned in which the source of illuminationis not worn by the subject but illuminates a non-ocular site, forexample, partially-illuminated bed linens.

[0077] Energy to operate the aforementioned devices may be provided by avariety of power sources that would enable the devices to be stationaryor portable, for example a standard AC outlet or a battery.

[0078] We have described a variety of specific embodiments of theinvention, but the method and device are not limited to theseembodiments. The claims set forth below incorporate the full scope anddefinition of the invention.

What is claimed is:
 1. A method of resetting a human circadian clockcomprising the step of exposing a non-ocular region of a human subjectto a non-solar photic stimulation during one or more circadian cycles toreset the human circadian clock.
 2. The method according to claim 1further comprising the step of assessing a time when a daily minimumbody temperature for the human subject occurs, wherein said step ofexposing the non-ocular region begins at an exposure time dependent uponthe assessed time.
 3. The method according to claim 2 wherein said stepof exposing the non-ocular region begins before the assessed time. 4.The method according to claim 3 wherein said step of exposing thenon-ocular region begins within about six hours prior to the assessedtime.
 5. The method according to claim 2 wherein said step of exposingthe non-ocular region begins after the assessed time.
 6. The methodaccording to claim 5 wherein said step of exposing the non-ocular regionbegins within six hours after the assessed time.
 7. The method accordingto claim 1 wherein said step of exposing the non-ocular region occurswhile the human subject is awake.
 8. The method according to claim 1wherein said step of exposing the non-ocular region occurs while thehuman subject is asleep.
 9. The method according to claim 1 wherein saidstep of exposing the non-ocular region lasts for a duration ranging frombetween about 15 minutes to about 12 hours.
 10. The method according toclaim 9 wherein the duration of said non-ocular exposure is about threehours.
 11. The method according to claim 1 wherein said non-solar photicstimulation has an intensity between about 15 lux to about 150,000 lux.12. The method according to claim 11 wherein said non-solar photicstimulation has an intensity between about 10,000 lux to about 13,000lux.
 13. The method according to claim 1 wherein said non-solar photicstimulation has a bandwidth in the visible spectrum.
 14. The methodaccording to claim 13 wherein said non-solar photic stimulation has abandwidth between about 455 nanometers (nm) and 540 nm.
 15. The methodaccording to claim 1 wherein the given number of circadian cycles isone.
 16. The method according to claim 1 wherein the given number ofcircadian cycles is two or more.
 17. The method according to claim 1wherein the non-ocular region of the human subject has ample surfacevasculature.
 18. The method according to claim 19 wherein the non-ocularregion is a popliteal region of the human subject.
 19. The methodaccording to claim 1 wherein said step of exposing the non-ocular regionis used to treat a circadian rhythm sleep disorder.
 20. The methodaccording to claim 19 wherein said step of exposing the non-ocularregion is used to treat the circadian rhythm sleep disorder resultingfrom transmeridian travel (jet-lag).
 21. The method according to claim19 wherein said step of exposing the non-ocular region is used to treatShift Work Sleep Disorder.
 22. The method according to claim 19 whereinsaid step of exposing the non-ocular region is used to treat AdvancedSleep Phase Syndrome (ASPS).
 23. The method according to claim 19wherein said step of exposing the non-ocular region is used to treatDelayed Sleep Phase Syndrome (DSPS).
 24. The method according to claim19 wherein said step of exposing the non-ocular region is used to treatNon-24-Hour Sleep-Wake Disorder.
 25. The method according to claim 19wherein said step of exposing the non-ocular region is used to treatIrregular Sleep-Wake Pattern.
 26. The method according to claim 1wherein said step of exposing the non-ocular region is used to treatsleep and circadian rhythm disorders associated with blindness.
 27. Themethod according to claim 1 wherein said step of exposing the non-ocularregion is used to treat sleep and circadian rhythm disorders inindividuals for whom ocular light exposure is contraindicated.
 28. Amethod of enhancing nighttime alertness and performance in a humansubject comprising the step of exposing a substantially non-ocularregion of the human subject to a non-solar photic stimulation during oneor more circadian cycles.
 29. The method according to claim 28 whereinsaid step of exposing the non-ocular region is used to enhance alertnessand performance of workers on rotating shift work schedules.
 30. Themethod according to claim 28 wherein said step of exposing thenon-ocular region is used to enhance alertness and performance ofindividuals working permanent work schedules.
 31. The method accordingto claim 28 wherein said step of exposing the non-ocular region lastsfor a duration ranging from between about 15 minutes to about 12 hours.32. The method according to claim 28 wherein said non-solar photicstimulation has an intensity between about 15 lux to about 150,000 lux.33. The method according to claim 28 wherein said non-solar photicstimulation has a bandwidth in the visible spectrum.
 34. The methodaccording to claim 28 wherein the non-ocular region of the human subjecthas ample surface vaculature.
 35. The method according to claim 28wherein the non-ocular region is a popliteal region of the humansubject.
 36. A method of resetting a human circadian clock comprisingthe steps of: assessing a time when a minimum body temperature for ahuman subject; and exposing a substantially non-ocular region of thehuman subject to a non-solar photic stimulation for one or morecircadian cycles to reset the human circadian clock at an exposure timedependent upon the assessed time.
 37. The method according to claim 36wherein said step of exposing the non-ocular region begins before theassessed time.
 38. The method according to claim 36 wherein said step ofexposing the non-ocular region begins about six hours prior to theassessed time.
 39. The method according to claim 36 wherein said step ofexposing the non-ocular region begins after the assessed time.
 40. Themethod according to claim 39 wherein said step of exposing thenon-ocular region begins within six hours after the assessed time. 41.The method according to claim 36 wherein said step of exposing thenon-ocular region occurs while the human subject is awake.
 42. Themethod according to claim 36 wherein said step of exposing thenon-ocular region occurs while the human subject is asleep.
 43. Themethod according to claim 36 wherein said step of exposing thenon-ocular region lasts for a duration ranging from between about 15minutes to about 12 hours.
 44. The method according to claim 43 whereinthe duration of said non-ocular exposure is about three hours.
 45. Themethod according to claim 36 wherein said non-solar photic stimulationhas an intensity between about 15 lux to about 150,000 lux.
 46. Themethod according to claim 45 wherein said non-solar photic stimulationhas an intensity between about 10,000 lux to about 13,000 lux.
 47. Themethod according to claim 36 wherein said non-solar photic stimulationhas a bandwidth in the visible spectrum.
 48. The method according toclaim 47 wherein said non-solar photic stimulation has a bandwidthbetween about 455 nm and 540 nm .
 49. The method according to claim 36wherein the number of circadian cycles is one.
 50. The method accordingto claim 36 wherein the number of circadian cycles is two or more. 51.The method according to claim 36 wherein the non-ocular region of thehuman subject has ample surface vasculature.
 52. The method according toclaim 51 wherein the non-ocular region is a popliteal region of thehuman subject.